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Modeling Neuronal Death and Degeneration in Mouse Primary Cerebellar Granule Neurons
Published on: November 6, 2017
Microglial cGAS-STING-C1q axis mediates dopaminergic synaptic pruning and motor dysfunction in Mn-induced
Yang Hu1, Honggang Chen1, Jianjie Zhao1
1Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
Abstract:
Environmental manganese (Mn) overexposure is a recognized risk factor for Parkinsonian-like neurodegeneration. Although synaptic loss is a crucial pathological hallmark of Mn neurotoxicity, the underlying cellular and molecular mechanisms are not fully understood. We demonstrate that Mn exposure induces motor dysfunction through aberrant microglial-mediated synaptic pruning. Pharmacological depletion of microglia effectively restores synaptic density and ameliorates motor deficits, establishing microglia as the primary drivers of this synaptic pathology. Mechanistically, Mn2 + activates the cGAS-STING pathway in microglia, which orchestrates the secretion of complement factor C1q and initiates the C1q/C3-CR3 complement cascade. This neuroimmune signaling results in complement-dependent tagging of dopaminergic synapses, triggering their targeted engulfment by activated microglia and consequent synaptic loss. Notably, blocking the STING pathway or neutralizing C1q function significantly attenuated excessive synaptic phagocytosis and prevented dopaminergic synapse loss, rescuing motor dysfunction in Mn-exposed mice. Together, our findings identify the cGAS-STING-C1q axis as a critical molecular driver of pathological synaptic pruning, highlighting a potential therapeutic strategy for treating neurological dysfunction in Mn-induced Parkinsonism.
Insights
Manganese (Mn) exposure causes Parkinsonian-like symptoms by triggering microglia to excessively prune synapses. Targeting the cGAS-STING-C1q pathway in microglia may prevent this neurodegeneration.
Area of Science:
- Neuroscience
- Toxicology
- Immunology
Background:
- Environmental manganese (Mn) overexposure is linked to Parkinsonian-like neurodegeneration.
- Synaptic loss is a key feature of Mn neurotoxicity, but mechanisms remain unclear.
Purpose of the Study:
- To elucidate the cellular and molecular mechanisms of Mn-induced synaptic loss and motor deficits.
- To identify potential therapeutic targets for Mn neurotoxicity.
Main Methods:
- Investigated Mn exposure effects on motor function and synaptic integrity in mice.
- Utilized microglial depletion and pharmacological inhibition of the cGAS-STING pathway.
- Analyzed the role of complement factor C1q in Mn-induced neuroinflammation and synaptic pruning.
Main Results:
- Mn exposure caused motor dysfunction via microglial-mediated synaptic pruning.
- Mn activated the cGAS-STING pathway in microglia, leading to C1q secretion and complement cascade activation.
- Blocking STING or C1q function rescued synaptic density and motor deficits.
Conclusions:
- The cGAS-STING-C1q axis drives pathological synaptic pruning in Mn neurotoxicity.
- Microglia are critical mediators of Mn-induced synaptic pathology.
- Targeting this pathway offers a potential therapeutic strategy for Mn-induced Parkinsonism.
